Method of Treating Corneal Opacities and Scarring

Abstract

Provided herein are methods of treating corneal opacities in patients, such as neonates, including administering to the patient's eye or cornea a ZBTB7B and/or granulin polypeptide, and/or knocking down expression of HAS2 and/or HYAL1 in the patient's eye or cornea.

1 . A method of treating corneal fibrosis in a patient, comprising, reducing expression of HYAL1 and/or HAS2 in the eye of the patient. 
     
     
         2 . The method of  claim 1 , comprising knocking down expression of HYAL1 and/or HAS2 in the eye of the patient. RNAi agent 
     
     
         3 . The method of  claim 2 , comprising administering an RNAi agent and/or an antisense agent to the eye of the patient in an amount effective to treat corneal opacity in the patient. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 3 , wherein the RNAi agent is administered to the patient's eye by administration to the patient's eye of a nucleic acid comprising a gene for expressing the RNAi agent. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , comprising knocking down HYAL1 in the eye of the patient. 
     
     
         8 . The method of  claim 1 , comprising knocking down HAS2 in the eye of the patient. 
     
     
         9 . (canceled) 
     
     
         10 . A method of treating corneal fibrosis in a patient, comprising, administering a granulin polypeptide and/or a ZBTB7B polypeptide to a patient's eye, in an amount effective to reduce corneal fibrosis in the patient. 
     
     
         11 . The method of  claim 10 , comprising administering a granulin polypeptide to a patient's eye, in an amount effective to reduce corneal opacity, corneal fibrosis, or corneal scarring in the patient. 
     
     
         12 . The method of  claim 11 , wherein the granulin polypeptide comprises or consists of:
 the amino acid sequence of SEQ ID NO: 11,   an amino acid sequence having at least 70, 80, 90, 95, 98, or 99% sequence identity or similarity to SEQ ID NO: 11, or   an amino acid sequence comprising one or more granulin motifs, such as X 2-3 CX 5-6 CX 5 CCX 8 CCX 6 CCX 5 CCX 4 CX 5-6 CX 2  or X 3 CX 6 CX 5 CCX 7 CC, where each instance of X is, independently, any amino acid, or the granulin polypeptide has the amino acid sequence of any one of SEQ ID NOS: 1-10 and 19-24, or a sequence having at least 70, 80, 90, 95, or 98% sequence identity or similarity to any one of SEQ ID NOS: 1-10, 19, or 20.   
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 11 , wherein the granulin polypeptide is a granulin 4, granulin 6, or granulin 7 polypeptide, or a combination of any of the preceding. 
     
     
         15 . The method of  claim 11 , wherein a nucleic acid is administered to the patient's eye, comprising a gene for expressing the granulin polypeptide in the patient's eye, to produce the granulin polypeptide in the patient's eye or an mRNA encoding the granulin polypeptide is administered to the patient's eye to produce the granulin polypeptide in the patient's eye. 
     
     
         16 - 18 . (canceled) 
     
     
         19 . The method of  claim 10 , comprising administering a ZBTB7B polypeptide to a patient's eye, in an amount effective to reduce corneal opacity, corneal fibrosis, or corneal scarring in the patient. 
     
     
         20 . The method of  claim 19 , wherein the ZBTB7B polypeptide has the amino acid sequence of SEQ ID NO: 13, or a sequence having at least 70, 80, 90, 95, 98, or 99% sequence identity or similarity to SEQ ID NO: 13. 
     
     
         21 . The method of  claim 19 , wherein a nucleic acid is administered to the patient's eye, comprising a gene for expressing the ZBTB7B polypeptide in the patient's eye, to produce the ZBTB7B polypeptide in the patient's eye or an mRNA encoding the ZBTB7B polypeptide is administered to the patient's eye to produce the ZBTB7B polypeptide in the patient's eye. 
     
     
         22 - 25 . (canceled) 
     
     
         26 . The method of  claim 10 , comprising administering both of a granulin polypeptide and/or a ZBTB7B polypeptide to the patient's eye. 
     
     
         27 . The method of  claim 10 , comprising both administering a granulin polypeptide and/or a ZBTB7B polypeptide to the patient's eye or cornea, and knocking down expression of HYAL1 and/or HAS2 in the patient's eye or in the patient's cornea. 
     
     
         28 . The method of  claim 1 , wherein the patient has a congenital corneal opacity, an acquired corneal opacity, corneal trauma, or a corneal transplant. 
     
     
         29 - 31 . (canceled) 
     
     
         32 . The method of  claim 1 , wherein the patient has Fanconi anemia, Peters' anomaly (PA), sclerocornea, congenital hereditary endothelial dystrophy (CHED), congenital hereditary stromal dystrophy (CHSD), posterior polymorphous dystrophy (PPMD), congenital anterior staphyloma, granular corneal dystrophy, cystinosis, ichthyosis, trisomy 8 mosaicism, or Farber's disease. 
     
     
         33 . The method of  claim 1 , wherein the patient is a human. 
     
     
         34 . (canceled) 
     
     
         35 . A topical or parenteral pharmaceutical composition for delivery to the eye of a patient, comprising a granulin polypeptide and/or a ZBTB7B polypeptide, a nucleic acid encoding a granulin polypeptide and/or a nucleic acid encoding ZBTB7B polypeptide, an antisense or RNAi agent for knocking down expression of HYAL1 and/or HAS2 in the patient's eye or in the patient's cornea, and/or a nucleic acid encoding RNAi agent for knocking down expression of HYAL1 and/or HAS2 in the patient's eye or in the patient's cornea, and a pharmaceutically acceptable excipient or carrier.